Aminomethyl-chroman and -thiochroman compounds

ABSTRACT

The present invention includes compounds represented by the formula: ##STR1## wherein X is O or S; 
     R 1  and R 2  are independently selected from the group consisting of hydrogen, hydroxy, halo, loweralkoxy, thioalkoxy and loweralkyl; or R 1  and R 2  taken together can form a methylenedioxy or ethylenedioxy bridge; 
     R 3  is loweralkyl; 
     R 4  is selected from ##STR2## wherein Y is O or S, R 6  is hydrogen, methoxy or halo and m is 0 or 1l R 5  is hydrogen, loweralkyl, phenyl or substituted phenyl wherein the phenyl ring is substituted with one, two or three substituents independently selected from loweralkyl, halo, hydroxy, loweralkoxy, amino and thioalkoxy; and 
     R 8  is hydrogen or R 3  and R 8  taken together form a pyrrolidine ring; or a pharmaceutically acceptable salt thereof.

This application is a division of co-pending application Ser. No.543,782 filed Jan. 13, 1989 as PCT/US89/00141, now U.S. Pat. No.5,089,519, which is a continuation-in-part of U.S. patent applicationSer. No. 144,363 filed Jan. 15, 1988, now abandoned.

Technical Field

This invention relates to alpha-2-adrenergic antagonists useful in thetreatment of depression, metabolic disorders (e.g. obesity or diabetes),glaucoma, migraine and hypertension.

BACKGROUND OF THE INVENTION

The adrenergic nervous system plays a major role in the innervation ofheart, blood vessel and smooth muscle tissue. Compounds capable ofinteracting with receptor sites within the adrenergic nervous system caninitiate a variety of physiological responses, includingvasoconstriction, vasodilation, and increased or decreased heart rate(chronotropic), contractility (inotropic) and metabolic activity. In thepast, various adrenergic compounds have been employed to affect theseand other physiological responses. However, many adrenergic compounds donot possess significant selectivity to enable desirable interactionswith adrenergic receptor sites. That is, these adrenergic compounds donot demonstrate a high degree of specificity for differing receptortypes within the adrenergic nervous system in order to obtain a desiredphysiological response separate from other possible, and perhaps lessdesirable, responses of the system.

Disclosure of the Invention

It has now been determined that a new class of compounds, as hereindefined, demonstrate an ability to selectively inhibit (antagonists)alpha-2-adrenergic receptors which are mainly distributed on themembranes of central and peripheral adrenergic neurons and on thetissues innervated thereby.

Through inhibitory interaction with the alpha-adrenergic receptor in theperipheral nervous system, one can modulate the function of adrenergicneurons and hemodynamic equilibrium which is therapeutically useful in amultitude of cardiovascular indications such as hypertension, congestiveheart failure, and a variety of vascular spastic conditions.Furthermore, the alpha-adrenergic antagonists are useful in certainneurological and psychiatric disorders such as depression.

The present invention includes compounds represented by the formula:##STR3## wherein X is 0 or S; R₁ and R₂ are independently selected fromthe group consisting of hydrogen, hydroxy, halo, loweralkoxy, thioalkoxyand loweralkyl; or R₁ and R₂ taken together can form a methylenedioxy orethylenedioxy bridge;

R₃ is loweralkyl;

R₄ is selected from ##STR4## wherein Y is 0 or S, R₆ is hydrogen,methoxy or halo and m is 0 or 1; R₅ is hydrogen, loweralkyl, phenyl orsubstituted phenyl wherein the phenyl ring is substituted with one, twoor three substituents independently selected from loweralkyl, halo,hydroxy, loweralkoxy, amino and thioalkoxy; and

R₈ is hydrogen or R₃ and R₈ taken together form a pyrrolidine ring; or apharmaceutically acceptable salt thereof.

It will be appreciated that the compounds of the present inventioncontain asymmetric carbon atoms and it is to be understood that theinvention includes both the racemic mixture as well as the opticallyactive derivatives.

As used herein, the term "loweralkoxy" refers to alkoxy groupscontaining 1 or 2 carbon atoms.

As used herein, the term "thioalkoxy" refers to --SR" wherein R" is analkyl residue containing 1 or 2 carbon atoms.

As used herein, the term "loweralkyl" means straight or branched chainsaturated hydrocarbon radicals having 1 to 3 carbon atoms, such asmethyl, ethyl, n-propyl and iso-propyl.

As used herein, the term "substituted phenyl" means a phenyl ring withone, two or three substituents independently selected from loweralkyl,halo, hydroxy, loweralkoxy, amino and --SR₇ wherein R₇ is loweralkyl.

As used herein, the term "halo" or "halogen" means fluorine, iodine,bromine or chlorine.

The term "pharmaceutically acceptable salts" refers to thepharmaceutically acceptable, relatively nontoxic, inorganic or organicacid addition salts of the compounds of this invention. These salts canbe prepared in situ during the final isolation and purification of thecompounds, or by separately reacting the free base with a suitableorganic or inorganic acid. Representative salts include thehydrochloride, hydrobromide, sulfate, phosphate, nitrate, bisulfate,acetate, oxalate, valerte, oleate, palmitrate, methanesulfonate,stearate, laurate, borate, benzoate, lactate, phosphate, tosylate,citrate, maleate, fumarate, succinate, tartrate, napsylate and the likeIt will be apparent to those skilled in the art that, depending upon thenumber of available amino groups for salt formation, the salt of thisinvention can be per N-salts.

The compounds of the present invention can be prepared as illustrated inScheme 1.

As seen in Scheme 1, starting with the desired 4-chromanone derivative,treatment with trimethylsilyl cyanide, followed by dehydration withp-TsOH, affords the desired chromene derivative 2. Reduction to theaminomethyl derivative is accomplished with Raney Nickel (RaNi) orsodium borohydride followed by diborane, to give 3. R₃ can be introducedusing the appropriate carboxylic acid or ester, activated ester or acidhalide derivatives thereof, followed by reduction of the resulting amidebond. Acid halide derivatives include the acid chloride. Esters includethe methyl and ethyl esters. Activated ester derivatives includeactivated esters commonly used by those skilled in the art foractivating carboxylic acid groups for coupling with an amine to form anamide bond including, but not limited to, formic and acetic acid derivedanhydrides, anhydrides derived from alkoxycarbonyl halides such asisobutyloxycarbonylchloride and the like, N-hydroxysuccinimide derivedesters, N-hydroxyphthalimide derived esters, N-hydroxybenzotriazolederived esters, 4-nitrophenol derived esters, 2,4,5-trichlorophenolderived esters and the like. In particular, N-alkylation of 3 isaccomplished with ethylformate or acetic anhydride, followed by diboranereduction, to give 4. The R₄ containing alkyl group can be introducedusing the appropriate carboxylic acid or ester, activated ester or acidhalide derivatives thereof as defined herein, followed by reduction ofthe resulting amide bond. In particular, dicyclohexylcarbodiimidepromoted coupling of 4 with the appropriately substituted carboxylicacid, followed by reduction with lithium aluminum hydride orborane-tetrahydrofuran complex, affords the desired compound 5.

The compounds of the invention which contain a pyrrolidine ring can beprepared as illustrated in Scheme II.

As seen in Scheme II, starting with the previously described chromenederivative 2, reduction with sodium borohydride followed by hydrolysisof the resulting unsaturated nitrile with potassium hydroxide inrefluxing ethylene glycol affords the desired carboxylic acid 6. Thepyrrolidine substituent can be introduced via reaction with thecarboxylic acid or an acid halide, ester or activated ester derivativeas defined herein. In particular, dicyclohexylcarbodiimide promotedcoupling followed by reduction of the resulting amide with lithiumaluminum hydride or borane-tetrahydrofuran complex affords the desiredcompound 7. ##STR5##

The foregoing may be better understood in connection with the followingexamples

EXAMPLE 1 7-Methoxy-4-cyano chrom-3-ene

7-Methoxy-4-chromanone (7 g) was added to trimethylsilyl cyanide (TMSCN)(7 ml), CH₃ CN (10 ml) and a catalytic amount of ZnI₂ and refluxed for 2hrs. The reaction was cooled, evaporated to dryness, then isopropylalcohol saturated with HCl(g) (100 ml) was added and this solutionrefluxed 2 hrs. The reaction was cooled, evaporated to dryness, andsaturated aqueous NaCl added. This was then extracted with CH₂ Cl₂, theorganic layer separated, dried (Na₂ SO₄), filtered and evaporatedaffording 7.1 g of product. IR(CHCl₃): 2218 cm⁻¹.

EXAMPLE 2 4-(Aminomethyl)-7-methoxy chroman

The product from Example 1 was hydrogenated with RaNi in MeOH and NH3 at4 atm. pressure and gave the desired product, (M+H)⁺ 194.

¹ H NMR(CDCl₃): 2.0 (m, 1H); 2.5 (m,2H); 2.95 (m,2H); 3.8 (s,2H); 4.2(m,2H); 6.4-7.4 (m,3H).

EXAMPLE 3 4-((N-Methylamino)methyl)-7-methoxy chroman

The product from Example 2 (5 g) was added to ethylformate (10 ml) andtoluene (100 ml) then refluxed for 21/2 hrs. The solution was evaporatedto dryness and then tetrahydrofuran (THF) (100 ml) and BH₃.THF 25.9 mlof a IM THF solution) was added followed by heating for 11/2 hrs. Thereaction was cooled and 6N HC1 (20 ml) was carefully added followed byheating for 1 hr. The THF was evaporated and the reaction made basicwith aqueous KOH. The reaction was extracted with CH₂ Cl₂, the organiclayer then separated, dried (MgSO₄), filtered and evaporated. Theresidue was chromatographed on silica gel and eluted with (EtOAc:H₂O:HCO₂ H) (16:2:2), giving the product (1.4 g). Mass spec: (M+H)⁺ 208 ¹H NMR(CDCl₃): 2.0 (m,2H); 2.49 (s,3H); 2.8 (m,2H); 3.75 (s,3H); 4.2(m,1H); 6.38-7.25 (m,3H).

EXAMPLE 44-((N-Methylamino)methyl-N-(2-(m-chlorophenyl)ethyl))-7-methoxy chromanhydrochloride

The product from Example 3 (1.4 q) was added to dicyclohexylcarbodiimide(DCC) (1.3 g), 1-hydroxybenzotriazole hydrate (1.62 g),m-chlorophenylacetic acid (1.02 g) and dry THF (40 ml). The reaction wasstirred at room temperature overnight, then filtered and evaporated todryness, giving the desired amide. The amide was reduced with BH₃.THF(1M THF solution), followed by treatment with methanolic HC1, to givethe desired product, m.p. 185°-86° C., 1.5 g. Mass spec: (M+H)⁺ 346.Anal.Calcd. for C₂₀ H₂₄ :C1NO₂ : C 62.83; H 6.33; N 3.66. Found: C62.65; H 6.60; N 3.64. ¹ H NMR(DMSO-d₆): 2.0-2.4 (m,2H); 2.9 (m,2H);3.1-3.5 (m,4H); 3.7 (s,3H); 4.15 (m,1H); 6.3-7.5 (m,7H).

EXAMPLE 5 4-((N-Ethylamino)methyl)-7-methoxy chroman

The product from Example 2 was reacted as described in Example 3replacing ethylformate with acetic anhydride, giving the desiredproduct, (M+H)⁺ 222. ¹ H NMR(CDCl₃): 1.15 (t,3H); 2.05 (m,2H); 2.6-2.0(m,4H); 3.75 (s,3H); 4.2 (m,1H), 6.3-7.1 (m,3H).

EXAMPLE 6 4-((N-Ethylamino)methyl-N-(2-(m-chlorophenyl)ethyl))-7-methoxychroman hydrochloride

The product from Example 5 was reacted as described in Example 4 to givethe desired product, m.p. 148°-149° C. Mass spec: (M+H)⁺ 360.Anal.Calcd. for C₂₁ H₂₇ Cl₂ NO₂.1/2 H₂ O: C 62.22; H, 6.96; N 3.46;Found: C 61.87; H 6.68; N 3.38. ¹ H NMR(DMSO-d₆); 1.3 (m,3H); 2.2(m,2H); 3.0-3.6 (m,6H); 3.7 (s,3H); 4.2 (m,1H); 6.3 7.5 (m,7H).

EXAMPLE 7 4-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-7-methoxychroman hydrochloride

Using the procedure described in Example 4, but replacingm-chlorophenylacetic acid with 2-thiophene acetic acid and the productof Example 3 gave the desired product, m.p. 223°-224° C. Anal. calcd.for C₁₈ H₂₄ C1NO₂ S: C 61.09; H 6.84; N 3.96; Found: C 61.17; H 6.82; N3.93.

EXAMPLE 8 4-((N-Methylamino)methyl-N-(2-(2-furyl)ethyl))-7-methoxychroman hydrochloride

Using the product of Example 3 and the procedure described in Example 4,but replacing m-chlorophenylacetic acid with 2-furylacetic acid andreplacing the BH₃.THF reduction with a lithium aluminum hydridereduction gave the desired compound.

EXAMPLE 9 7,8-Dimethoxy-4-cyano thiochrom-3-ene

Using the procedure of Example 1, but replacing 7-methoxy-4-chromanonewith 7,8-dimethoxy-4-thiochromanone gave the desired product, m.p.134°-35° C. Mass spec: (M+H)⁺ 233. IR(CHCl₃): 2215 cm⁻¹ (CN).

EXAMPLE 10 7,8-Dimethoxy-4-cyano thiochroman

The product from Example 9(8 g) was dissolved in EtOH (150 ml), thenNaBH₄ (6.48 g) was added. The reaction was refluxed for 1 hr, cooled andevaporated to dryness. A 10% aqueous HCl solution was added, followed bya methylene chloride extraction. The organic layer was separated, dried(Na₂ SO₄), filtered and evaporated giving the desired product, m.p.116°-118° C., 5.25 g. Mass spec: (M+H)⁺ 235 IR(CHCl₃): 2220⁻¹ cm (CN).

EXAMPLE 11 4-(Aminomethyl)-7,8-d1methoxy thiochroman hydrochloride

The product from Example 10 (2.35 g) was dissolved in dry THF (50 ml)then 1M BH₃.THF in THF (56 ml) was added, followed by refluxing for 3hrs. The reaction was cooled and methanolic HC1 carefully added. Thesolvents were removed affording after recrystallization from EtOH/Et₂ Oa white solid, 1.9 g, m.p. 254°-55° C. Mass spec.: (M+H)⁺ 239. ¹ HNMR(DMSO-d₆): 1.8 (m,2H); 2.4 (m,2H); 2.8-3.1 (m,5H); 3.2 (m,2H);3.65-3.8 (d, 6H); 6.8 7.0 (q,2H).

EXAMPLE 12 4-((N-Methylamino)methyl)-7,8-dimethoxy thiochromanhydrochloride

Using the procedure of Example 3 and the product from Example 11, thedesired product was obtained, m.p. 176°-77° C. Mass spec.: (M+H)⁺ 253 ¹H NMR(DMSO-d₆): 1.8 (m,2H); 2.4 (m,2H); 2.8-3.2 (m,5H); 3.3 (m,2H);3.6-3.8 (d,6H); 6.8-7.0 (q,2H).

EXAMPLE 134-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-7,8-dimethoxythiochroman hydrochloride

2-Thiopheneacetic acid (12.4 g), and NaBH₄ (1.4 g) were added to toluene(50 ml) and stirred at room temperature for 2 hrs. Then the product(free base) (1.6 q) from Example 12 was added and the reaction refluxedfor 2 hrs., then cooled. Toluene, containing aqueous 10% NaOH was addedand the layers separated. The organic layer was dried and evaporated todryness. The residue was dissolved in EtOH and ethereal HC1 added. Thesolid was filtered and recrystallized from EtOH/Et₂ O, affording thedesired product, m.p. (226°-27° C., 1.46 g. Mass spec.: (M+H)⁺ 363.Anal. Calcd. for C₁₉ H₂₆ C1NO₂ S₂ : H 57.05; H 6.55; N 3.5; Found: C56.43; H 6.24, N 3.06. ¹ H NMR(DMSO-d₆): 1.8 (m,2H); 2.55 (m,2H); 2.9(m,4H); 3.1 (m,2H); 3.4 (m,5H); 3.65-3.8 (d,6H); 6.88-7.4 (m,4H).

EXAMPLE 14 7-Methoxy-4-cyano thiochromene

Using the procedure of Example 1 but replacing 7-methoxy-4-chromanonewith 7-methoxy-4-thiochromanone gave the desired product, M⁺ 203IR(CHCl₃): 2020⁻¹ cm (CN).

EXAMPLE 15 4-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-7-methoxythiochroman hydrochloride

Using the product from Example 14 and following the procedures describedin Examples 10-13 gave the desired compound, m p. 217°-18° C. Anal.Calcd. for C₁₈ H₂₄ C1NOS2: C 58.44; H 6.54; N 3.79; Found: C 58.62; H6.75; N 3.64. ¹ H NMR(DMSO-d₆): 1.85 (m,1H); 2.65 (m,2H); 2.9 (m,2H);3.35 (m,6H) 3.35 (s,3H); 3.7 (s,3H) 6.6-7.4 (m,6H).

EXAMPLE 16

Using the product from Example 14 and following the procedures describedin Examples 10-13 but replacing 2-thiopheneacetic acid with the desiredreadily available carboxylic acid, the following compounds wereprepared:

6a) 4-[(N-Methylamino)methyl-N-(2-(phenyl)ethyl)]-7-methoxy thiochromanhydrochloride.

16b) 4-[(N-methylamino)methyl-N-(2-(m-fluorophenyl) ethyl)]-7-methoxythiochroman hydrochloride.

16c) 4-[(N-methylamino)methyl-N-(2-(m-chlorophenyl) ethyl)]-7-methoxythiochroman hydrochloride.

EXAMPLE 17 7-Methoxy-8-methyl-4-cyano chrom-3-ene

Using the procedure described in Example 1 but replacing7-methoxy-4-chromanone with 7-methoxy-8-methyl-4-chromanone gave thedesired product. IR(CHCl₃): 2240 cm⁻¹ (CN).

EXAMPLE 18 4-((N-Methylamino)methylN-(2-(m-chlorophenyl)ethyl))-7-methoxy-8-methyl chroman hydrochloride

Using the product from Example 17 and following the procedures describedin Examples 2-4 gave the desired compound.

EXAMPLE 19 7-Chloro-4-cyano chrom-3-ene

Using the procedure described in Example 1 but replacing7-methoxy-4-chromanone with 7-chloro-4-chromanone gave the desiredcompound.

EXAMPLE 20 4-(Aminomethyl)-7-chloro chroman hydrochloride

Using the product from Example 19 and following the procedures describedin Examples 10 and 11 gave the desired compound.

EXAMPLE 21 4-((N-Methylamino)methyl)-7-chloro chroman hydrochloride

Using the procedure of Example 3 and the product from Example 20 gavethe desired compound.

EXAMPLE 224-((N-Methylamino)methyl-N-(2-(m-methoxyphenyl)ethyl))-7-chloro chromanhydrochloride

Using the product from Example 21 and the procedure described in Example4 but replacing m-chlorophenylacetic acid with m-methoxyphenylaceticacid gave the desired compound.

EXAMPLE 23 4-(Aminomethyl)-7,8-dimethoxy chroman hydrochloride

Using the procedures described in Examples 1-3, but replacing 7-methoxy4-chromanone with 7,8-dimethoxy-4-chromanone, gave the desired product.

EXAMPLE 24 4-((N-Methylamino)methyl)-7,8-dimethoxy chroman hydrochloride

Using the procedure of Example 3 with the product of Example 23 gave thedesired compound.

EXAMPLE 254-((N-Methylamino)methyl-N-(2-(m-fluorophenyl)ethyl))-7,8-dimethoxychroman hydrochloride

Using the product of Example 24 and the procedure described in Example4, but replacing m-chlorophenylacetic acid with m-fluorophenylaceticacid, gave the desired compound, m.p. 195°-197° C. Anal. cald. for C₂₁H₂₇ C1FNO₃ : C 63.71; H 6.87; N 3.54. Found: C 63.95; H 6.95; N 3.59.

EXAMPLE 26 4-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))7,8-dimethoxy chroman hydrochloride

Using the product of Example 24 and the procedure described in Example4, but replacing m-chlorophenylacetic acid with 2 thiopheneacetic acid,gave the desired compound, m.p. 232°-234° C. Anal. cald. for C₁₉ H₂₆C1NO₃ S: C 59.44; H 6.83; N 3.65. Found: C 59.41; H 6.76; N 3.64.

EXAMPLE 27 4-((N-Ethylamino)methyl)-7-methoxy-8-methyl chroman

Using the procedures described in Examples 1-3 and 5, but replacing7-methoxy-4-chromanone with 7-methoxy-8-methyl-4-chromanone, gave thedesired product, (M+H)⁺ 346. ¹ H NMR(CDCl₃): 1.15 (t,3H); 2.0 (m,2H);2.1 (s,3H); 2.8 (m,6H); 3.8 (s,3H); 4.2 (m,1H); 6.45-7.0 (q,2H).

EXAMPLE 284-((N-Ethylamino)methyl-N-(2-(2-thienyl)ethyl))-7-methoxy-8-methylchroman hydrochloride

The product of Example 27 was reacted as described in Example 4, butreplacing m-chlorophenylacetic acid with 2-thiopheneacetic acid, to givethe desired product, m.p. 175°-76° C. Anal. Calcd. for C₂₀ H₂₈ C1NO₂ S:C 62.89; H 7.39; N 3.67; Found C 62.60; H 7.41; N 3.63. ¹ HNMR(DMSO-d₆): 1.15 (m,3H); 1.95 (s,3H); 2.1 (m,2H); 2.3 (m,2H); 3.4(m,8H); 3.75 (s,3H); 4.2 (m,1H); 6.5-7.5 (m,5H).

EXAMPLE 29 4-((N-Methylamino)methyl)-2-phenyl-7-methoxy chromanhydrochloride

Using the procedures described in Examples 1, 10 and 11, but replacing7-methoxy-4-chromanone with 7-methoxy-2-phenyl-4-chromanone, gave thedesired product, (M+H)⁺ 284, m.p. 207°-208° C. Anal. Calcd. for C₁₈ H₂₂C1NO₂ : C 67.60; H 6.93; N 4.38; Found: C 67.46; H 6.83; N 4.33. ¹ HNMR(DMSO-d₆) 1.9 (m,3H); 2.6 (m,2H); 3.35 (s,3H); 3.7 (s,3H); 5.1(q,1H); 6.4-7.6 (m,8H).

EXAMPLE 304-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-7-methoxy-2-phenylchroman hydrochloride

The product of Example 29 was reacted as described in Example 4, butreplacing m-chlorophenylacetic acid with 2-thiopheneacetic acid, givingthe desired compound as an amorphous solid. Mass spec.: (M+H)⁺ 394 Analcald. for C₂₄ H₂₈ C1NO₂ S . 1/2H₂ O: % C 65.66; H 6.66; N 3.19. Found: %C 65.27; H 6.51; N 3.00.

EXAMPLE 31 4-((N-Methylamino)methyl)-7-methoxy-2-methyl chroman

Using the procedures described in Examples 1-3, but replacing7-methoxy-4-chromanone with 7-methoxy-2-methyl-4-chromanone, gave thedesired compound. (M+H)⁺ 220.

EXAMPLE 32 4-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))7-methoxy-2-methyl chroman hydrochloride

The product of Example 31 was reacted as described in Example 4,replacing m-chlorophenylacetic acid with 2-thiopheneacetic acid, givingthe desired compound.

EXAMPLE 334-((N-methylamino)methyl-N-(2-(m-methoxyphenyl)ethyl)-7-methoxy-2-methylchroman hydrochloride

The product of Example 31 was reacted as described in Example 4replacing m-clorophenylacetic acid with m-methoxyphenylacetic acid togive the desired product.

EXAMPLE 34 4-((N-Methylamino)methyl-N (2(m-fluorophenyl)ethyl))-7.8-dihydroxy chroman hydrobromide

The product of Example 25 was treated at -78° C. with BBr₃ in CH₂ Cl₂.The reaction mixture was allowed to warm to 0° C. and stirred for 3hours under nitrogen. The reaction mixture was cooled to -78° C., thencarefully quenched with MeOH. The reaction mixture was evaporated todryness, triturated with ether, and filtered to give the desiredproduct.

EXAMPLE 35 4-((N-Methylamino)methyl-N-(2(m-chlorophenyl)ethyl))-7-methoxy-2-phenyl chroman hydrochloride

The product of Example 29 was reacted as described in Example 4 toafford the desired compound.

EXAMPLE 364-((N-Methylamino)methyl-N-(2-(m-chlorophenyl)ethyl))-7-hydroxy-2-phenylchroman hydrobromide

The product of Example 35 was reacted as described in Example 34 to givethe desired compound.

EXAMPLE 37 7,8-Methylenedioxy-4-chromanone

To a solution of 2,3-methylenedioxyphenol (27 g) and N-methyl morpholine(19.6 g) in THF (100 ml) was added benzyl propiolate (38 g) over aperiod of 30 minutes with cooling. After the addition was complete thereaction was stirred at room temperature for 1.5 hours followed byconcentration The residue was taken up into Et₂ O (500 ml), washed with10% HCl (2×100 ml), dried over MgSO₄. filtered and concentrated. Thismaterial was subjected to hydrogenation with 10%Pd/C in methanol at 4atm. The reaction was filtered and concentrated. The resulting saturatedacid was dissolved into methanesulfonic acid (350 ml) and stirred for 24hours. The reaction was poured onto ice and extracted with CH₂ Cl₂. Theorganic layer was washed with saturated Na₂ CO₃, dried over MgSO₄,filtered and concentrated to provide the desired material.

EXAMPLE 384-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-7,8-methylenedioxychromanhydrochloride

Using the procedures in Examples 1-4 but replacing7-methoxy-4-chromanone with Example 37 and replacingm-chlorophenylacetic acid with thiopheneacetic acid afforded the desiredproduct.

EXAMPLE 394-((N-Methylamino)methyl-N-(2-phenethyl))-7,8-methylenedioxychromanhydrochloride

Using the procedures outlined in Example 38 but replacingthiopheneacetic acid with phenylacetic acid provided the desiredproduct.

EXAMPLE 404-((N-Ethylamino)methyl-N-(2-(2-thienyl)ethyl))-7,8-methylenedioxychromanhydrochloride

Using the procedures in Examples 1, 2, 5 and 4 but replacing7-methoxy-4-chromanone with Example 37 and replacingm-chlorophenylacetic acid with thiopheneacetic acid afforded the desiredproduct.

EXAMPLE 41 4-((N-Ethylamino)methyl-N (2 phenethyl))7,8-methylenedioxychroman hydrochloride

Using the procedures in Examples 1, 2, 5 and 4 but replacing7-methoxy-4-chromanone with Example 37 and replacingm-chlorophenylacetic acid with phenylacetic acid provided the desiredproduct.

EXAMPLE 42 7,8-Ethylenedioxy-4-chromanone

Using the procedure outlined in Example 37 but replacing2,3-methylenedioxyphenol with 2,3-ethylenedioxyphenol provided thedesired material.

EXAMPLE 434-((N-Methylamino)methyl-N-(2-(2-thienyl)ethyl))-7.8-ethylenedioxychromanhydrochloride

Using the procedures in Examples 1-4 but replacing7-methoxy-4-chromanone with Example 42 and replacingm-chlorophenylacetic acid with thiopheneacetic acid afforded the desiredproduct.

EXAMPLE 444-((N-Methylamino)methyl-N-(2-phenethyl))-7,8-ethylenedioxychromanhydrochloride

Using the procedures in Examples 1.4 but replacing7-methoxy-4-chromanone with Example 42 and replacingm-chlorophenylacetic acid with phenylacetic acid afforded the desiredproduct.

EXAMPLE 45 4-((N-Ethylamino)methyl-N(2-(2-thienyl)ethyl))-7,8-ethylenedioxychoman hydrochloride

Using the procedures in Examples 1, 2, 5 and 4 but replacing7-methoxy-4-chromanone with Example 42 and replacingm-chlorophenylacetic acid with thiopheneacetic acid afforded the desiredproduct.

EXAMPLE 46 4-((N-Ethylamino)methyl-N-(2-phenethyl))7,8-ethylenedioxychroman hydrochloride

Using the procedures in Examples 1, 2, 5 and 4 but replacing7-methoxy-4-chromanone with Example 42 and replacingm-chlorophenylacetic acid with phenylacetic acid provided the desiredproduct.

EXAMPLE 47 4-Carboxy-7,8-methylenedioxychroman

Using the procedure in Example 1, but replacing 7-methoxy-4-chromanonewih Example 37 afforded the unsaturated nitrile To a solution of thisnitrile (5.0 g) in ethanol (80 ml) was added in small portions sodiumborohydride (1.44 g). After the addition was complete the reaction washeated to reflux. After 12 hours, the reaction was cooled andconcentrated. The residue was taken up into 1 N HCl and CH₂ Cl₂ and thelayers separated. The organic phase was washed with water, brine, driedover MgSO₄, filtered and concentrated. The resulting material wasdissolved into ethylene glycol (42 ml) treated with 45% KOH (30 ml) andheated to reflux. After 3 hours the reaction was cooled with an icebath, diluted with ice/water and acidified with concentrated HCl. Theproduct was extracted with ethyl acetate (3×75 ml), washed with brine,dried over MgSO₄, filtered and concentrated to afford the desiredproduct.

EXAMPLE 48 7,8-Methylenedioxy-4-(3-(2-thienyl)pyrrolindino- 1-methyl)chroman hydrochloride

Using the procedure in Example 4 but replacing m-chlorophenylacetic acidwith Example 47 and Example 3 with 3-(2-thienyl)pyrrolidine afforded thedesired material.

EXAMPLE 49 7,8-Methylenedioxy 4-(3-phenylpyrrolindino-1-methyl) chromanhydrochloride

Using the procedure in Example 4 but replacing m-chlorophenylacetic acidwith Example 47 and Example 3 with 3-phenylpyrrolidine afforded thedesired material.

EXAMPLE 50 4-Carboxy-7,8-ethylenedioxychroman

Using the procedure in Example 47 but replacing Example 37 with Example42 provided the desired material.

EXAMPLE 51 7,8-Ethylenedioxy-4-(3-(2-thienyl)pyrrolindino-1-methyl)chroman hydrochloride

Using the procedure in Example 4 but replacing m-chlorophenylacetic acidwith Example 49 and Example 3 with 3-(2-thienyl)pyrrolidine afforded thedesired material.

EXAMPLE 52 7,8-Ethylenedioxy-4-(3-phenylpyrrolindino-1-methyl) chromanhydrochloride

Using the procedure in Example 4 but replacing m-chlorophenylacetic acidwith Example 49 and Example 3 with 3-phenylpyrrolidine afforded thedesired material.

The compounds were assessed for alpha-adrenergic receptor subtypeselectivity by use of radioligand binding techniques as describedpreviously (DeBernardis et. al. J. Med. Chem. 28, 1398 (1985)). Affinityfor the alpha-1-receptor was assessed using rat liver homogenates andthe radioligand [³ H]-prazosin; whereas for the alpha-2-receptor, ratcerebral cortices and the radioligand [³ H]-rauwolscine were utilized.Results obtained from the binding studies are shown in Table 1 for arepresentative sample of compounds disclosed herein.

                  TABLE 1                                                         ______________________________________                                        Radioligand Binding Data at alpha 1- and alpha                                2- Adrenoceptors for Representative Compounds                                          K.sub.i (nM)     alpha-2 - Selectivity                               Example #  alpha-1  alpha-2   K.sub.i alpha-1/K.sub.i alpha-2                 ______________________________________                                        4          260      24        11                                              6          1135     34        33                                              7          590      10        59                                              13          96      3         32                                              25         550      3         183                                             26         10000    5.8       1724                                            28         1000     34        29                                              ______________________________________                                    

The compounds of the invention can be administered in any effectivepharmaceutically acceptable form to warm blooded animals, e.g., in oral,parenteral or infusable dosage forms, or as a buccal or nasal spray.Suitable parenteral routes of administration include, for example,intramuscular, intravenous, intraperitoneal or subcutaneousadministration of the compounds.

In addition to the active compounds, compositions according to thisinvention for parenteral injection may comprise pharmaceuticallyacceptable sterile aqueous or nonaqueous solutions, suspensions oremulsions. Examples of suitable nonaqueous carriers, diluents, solventsor vehicles include propylene glycol, polyethylene glycol, vegetableoils, such as olive oil, and injectable organic esters such as ethyloleate. Such compositions may also contain adjuvants such as preserving,wetting, emulsifying, and dispersing agents. They may be sterilized, forexample, by filtration through a bacteria-retaining filter, or byincorporating sterilizing agents into the compositions. They can also bemanufactured in the form of sterile solid compositions which can bedissolved in sterile water, or other sterile injectable medium,immediately before use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound may be admixed with at least one inert diluent such as sucrose,lactose or starch. Such dosage forms may also comprise, as is normalpractice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirscontaining inert diluents commonly used in the art, such as water.Besides such inert diluents, compositions may also comprise adjuvants,such as wetting agents, emulsifying and suspending agents, andsweetening. flavoring and perfuming agents.

Actual dosage levels of active ingredient in the compositions of theinvention may be varied so as to obtain an amount of active ingredienteffective to obtain a desired therapeutic response for a particularcomposition and method of administration. The selected dosage leveltherefore depends upon the desired therapeutic effect, on the route ofadministration, on the desired duration of treatment and other factors.Generally, dosage levels of about 0.1 to about 200, more preferablyabout 0.5 to about 150 and most preferrably about 1 to about 125 mg ofactive ingredient per kg of body weight per day are administered orallyto a mammalian patient suffering from depression. If desired, the dailydose may be divided into multiple doses for administration, e.g., two tofour separate doses per day.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

What is claimed is:
 1. A compound of the formula ##STR6## wherein R₁ andR₂ are independently selected from the group consisting of hydrogen,hydroxy, halo, loweralkoxy, thioalkoxy, and loweralkyl;R₃ is loweralkyl;R₄ is selected from ##STR7## and wherein Y is O or S, R₆ is hydrogen,methoxy or halo, and m is 0 or 1; R₅ is hydrogen, loweralkyl, phenyl, orsubstituted phenyl wherein the phenyl ring is substituted with one, twoor three substituents independently selected from loweralkyl, halo,hydroxyl, loweralkoxy, amino, and thioalkoxy; and R₈ is hydrogen, or R₃and R₈ taken together form a pyrrolidine ring; with the proviso thatwhen R₄ is ##STR8## then R₃ and R₈ taken together form a pyrrolidinering; or a pharmaceutically acceptable salt thereof.
 2. A compound ofclaim 1 wherein R₁ is hydrogen or methoxy and R₂ is methoxy; R₃ ismethyl or ethyl; and R₄ is furyl, thienyl orR₃ and R₈ taken togetherform a pyrrolidinyl ring and R₄ is furyl, thienyl, phenyl or substitutedphenyl.
 3. A compound selected from the group consistingof:4-((N-methylamino)methyl-N-(2-(2-thienyl)ethyl)-7,8-dimethoxychroman; 4-((N-methylamino)methyl-N-(2-(2-thienyl)ethyl)-7-methoxychroman; 4-((N-methylamino)methyl-N-(2-(2-furyl)ethyl)-7-methoxychroman;4-((N-ethylamino)methyl-N-(2-(2-thienyl)ethyl)-7-methoxy-8-methylchroman;4-((N-methylamino)methyl-N-(2-(2-thienyl)ethyl)-7-methoxy-2-phenylchroman; and4-((N-methylamino)methyl-(2-(2-thienyl)ethyl)-7-methoxy-2-methylchroman; or a pharmaceutically acceptable salt thereof.
 4. Apharmaceutical composition for selectively inhibiting alpha-2-adrenergicreceptors comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim
 1. 5. A methodfor selectively inhibiting alpha-2-adrenergic receptors comprisingadministering to a patient in need, a therapeutically effective amountof a compound of claim
 1. 6. A method for treating depression comprisingadministering to a patient in need, a therapeutically effective amountof a compound of claim 1.